Epigenetics, characterized by the inheritance of regulatory information stored on chromosomes by means other than DNA sequence, is at the forefront of complex disease research. Epigenetics is a rich term that describes many phenomena, however the studies with the broadest disease relevance are those of environmentally-induced changes to gene expression states that are inherited through mitosis and/or meiosis. This transgenerational epigenetic inheritance is thought to account for accumulated disease risk in individuals, and for transmission of disease risk to offspring. Understanding how a disease state is epigenetically inherited is critically important to the NIH's mission ??to enhance health, lengthen life, and reduce illness and disability.? However, many data concerning the basic mechanisms of epigenetic inheritance in model organisms are inconsistent with how the epigenetic models are applied to human disease, and highlight major roadblocks in research. These data do not just challenge the models for epigenetic inheritance, they suggest that the way we think about epigenetic inheritance is the impediment. The serious and persistent roadblocks can be immediately removed by considering that transgenerational epigenetic defects are in fact caused by particular types of mutations: induced by the environment, high-frequency, and preferentially affecting speci?c regions of genomes that have pleiotropic regulatory and physiological effects. Considering this alternative explanation creates a paradigmatic con?ict because it doesn't challenge data, it questions the expectations of ?epigenetic,? and challenges how we approach the problem and identify the gaps that need to be ?lled by research. This Transformative Research Award proposal: (i) highlights the problems with the existing model for transgenerational ?epigenetic? inheritance, (ii) explains the data-supported alternative model that carries with it a new paradigm, (iii) explains why it is the paradigmatic con?ict that impedes research, (iv) demonstrates the utility of the alternative in solving current research problems, and (v) explains how acceptance of the paradigm will sidestep roadblocks and redirect research to better utilize precious resources. Two sets of experimental directions are planned. The ?rst set ? whether ?epigenetic? information is encoded at a gene, and whether ?epigenetic? information can distinguish two identical genes ? focuses on irreconcilable differences between the paradigms to determine which is valid. The second set ? the genetic basis of ?epigenetic? inheritance, and the differences between two cells that differ only in their ?epigenetic? status ? will advance our understanding of ?epigenetic? defects in disease. If my alternative paradigm is correct, these experiments will open new areas of research into (i) how intrinsically unstable repeat DNAs in the genome respond to environmental stress, disease, and mutation, (ii) how repeat DNAs in?uence expression of gene networks throughout the genome, and (iii) how defects in repeat DNA stability lead to permanent damage to the genome. These areas are expected to establish new approaches to prevent and treat complex diseases.